Myeloproliferative neoplasms or MPNs are a heterogeneous group of complex hematologic diseases, which share the common characteristic of myeloid cell overproduction. Mastocytosis, especially the systemic form of the disease, also known as systemic mastocytosis (SM) is considered a particularly difficult form of MPN to treat. Activating mutations of KIT are found in over 90% patients with SM, characterized by clonal expansion and accumulation of myelomastocytic progenitors within various tissues leading to organ failure and poor overall survival. With the exception of chronic myelogenous leukemia (CML), there are no effective therapies for MPNs. In the case of CML, targeting the tyrosine kinase BCR-ABL with imatinib (gleevec) or second generation tyrosine kinase (TK) inhibitors such as nilotinib and desatinib appears to be sufficient for treating most patients; however, a significant number of these patients go on to develop drug resistance. In contrast, in other types of MPNs, including SM, targeting the activated version of the receptor tyrosine kinase receptor KIT alone has been ineffective; particularly in patients that harbor the activating mutation of KIT in the catalytic domain, KITD816V, which are completely resistant to imatinib or second generation tyrosine kinase inhibitors. Recent studies in patients with mastocytosis have shown the presence of Tet2 mutations in ~30% patients. In these patients, mutations in Tet2 are associated with higher leukocyte counts, monocyte counts, serum tryptase levels, mast cell burden, splenomegaly and the presence of activating KIT mutation, KITD816V. Thus, Tet2 mutations are frequent in SM; they segregate with KITD816V and significantly influence the phenotype including overall survival and may help explain why anti-KITD816V therapy alone may not be effective for treating these patients. Our long range goal is to elucidate the aberrant signaling mechanism(s) induced by activating KIT mutations and epigenetic regulators such as Tet2 that promote pathologic over production of myeloid/mast cells in SM, with the intent of defining novel therapeutic targets for this disease. The objective of this application is to define the role of Tet2 and activating mutation of KIT and downstream pathways in the initiation and progression of mast cell growth, development and transformation utilizing state of the art mouse genetic models of SM and primary patient samples. Our proposed studies will provide unique insights into the physiologic significance of the in vivo interactions between Tet2 and the oncogenic KIT in regulating normal as well as abnormal myeloid/mast cell biology.